Tablet dosage form of clavulanic acid and amoxycillin comprising a trehalose excipient

ABSTRACT

Provided are tablet formulations in one embodiment comprising clavulanic acid or salt thereof, amoxycillin, and trehalose. The trehalose is, for example, amorphous anhydrous trehalose. The amorphous anhydrous trehalose is present in an amount, for example, of 5 to 50%. The formulation may further comprise, for example, desiccants, such as silica gel, or lubricants.

This invention relates to dosage forms for pharmaceutical preparationsof antibiotics, particularly but not exclusively incorporating theactive ingredients potassium clavulanate and amoxycillin trihydrate.These are referred to in this specification as “co-amoxiclav”formulations. Co-amoxiclav is the British approved name or pharmacyequivalent name for formulations containing amoxycillin trihydrate andpotassium clavulanate. The invention also reiazes to dosage forms ofother salts or derivatives of clavulanic acid in combination withbeta-lactam antibiotics.

Use of clavulanic acid in combination with beta-lactam antibiotics wasdisclosed in GB 1508977. WO92/19227 discloses tablet co-amoxiclavformulations comprising compacted granulates including intra-granularand extra-granular disintegrants.

GB-A-2005538 discloses co-amoxiclav formulations containing conventionalexcipients. U.S. Pat. No. 4,678,812 discloses replacement of mannitolwith trehalose in tablets for diagnostic applications.

Potassium clavulanate is the least hygroscopic of the pharmaceuticallyacceptable clavulanic acid salts. Nevertheless it is extremelyhygroscopic and liable to hydrolysis so that co-amoxiclav formulationsare prone to degradation on storage even under low humidity conditions.The presence of water of crystallisation of amoxycillin may contributeto instability of these dosage forms, accelerating the decompositiononce any degradation has commenced.

According to the present invention a tablet formulation comprises asactive ingredients a combination of clavulanic acid or salt thereof andamoxycillin with excipients comprising trehalose together with furtherexcipients including one or more binders, divalents, disintegrants andlubricants.

Trehalose (α-D-glucopyranosyl-α-D-glucopyranoside) is a naturallyoccurring, non-reducing disaccharide which was initially found to beassociated with the prevention of desiccation damage in certain plantsand animals which can dry out without damage and can revive whenrehydrated.

Trehalose used in accordance with this invention may be provided invarious physical forms. The forms of trehalose include trehalosedihydrate (TD) which is crystalline, amorphous trehalose (AT) which is avitreous form, and the anhydrous forms of trehalose, anhydrous amorphoustrehalose (AAT) and anhydrous crystalline trehalose (ACT). Powderedanhydrous trehalose may contain AAT and/or ACT. The term “trehalose”used in this specification refers to any physical form of trehaloseincluding anhydrous, partially hydrated, fully hydrated and mixtures andsolutions thereof. The term “anhydrous trehalose” refers to any physicalform of trehalose containing less than 2% water. The anhydrous forms oftrehalose may contain from 0 to 2% water and still retain superiorproperties in tabletLing. Amorphous trehalose (AT) contains about 2 to9% water and trehalose dihydrate (TD) contains about 9 to 10% water. Themanufacture and use of anhydrous trehalose from TD is disclosed in ourcopending application PCT/GB97/00367, the disclosure of which isincorporated into this specification by reference.

The use of trehalose, particularly amorphous anhydrous trehalose inco-amoxiclav solid dosage forms confers several advantages. Increasedstability of the active ingredients, particularly potassium clavulanateis obtained. Furthermore the anhydrous trehalose protects the activeingredients from ambient humidity and any residual humidity in theformulation after manufacture. The protection from humidity offered byanhydrous trehalose (AAT or ACT) may be due to absorption of water toproduce TD. This sequestration of water molecules from the activeingredients may decrease the exposure of the latter to moistureresulting in prolonged shelf life, particularly when a container isopened periodically for dispensing of some of the contents. AAT and ACThave the particular advantage that moisture is absorbed even at lowrelative humidities

Preferably the clavulanic acid salt is potassium clavulanate.

Particularly the amoxycillin is present as amoxycillin trihydrate.

Tablets of this invention may contain the active ingredients in anyconvenient amounts and weight ratios. For example the weight ratio maybe equivalent to amoxycillin/clavulanic acid in the range 12:1 to 1:1,preferably around 4:1 to 2:1, The proportion of active ingredients inthe tablets may be between the broad range of 20 to 90 preferably about30%. The total amount of the active ingredients may be selected to giveconventional dosages including higher amounts for twice dailyadministration as disclosed in WO95/28927. Proportions and amounts usedin this specification are by weight unless indicated otherwise.

The amount of anhydrous trehalose (AAT or ACT) may be 5 to 50% ,preferably 7 to 15% more preferably about 10%.

In preferred embodiments of the invention the active ingredients,especially antibiotics, preferably clavulanate, are combined with thetrehalose as a preliminary step before blending with the othercomponents for tabletting. Dry compaction by slugging with anhydroustrehalose (AAT or ACT) may be employed, (preferably in 5 to 20% of asilica binder, conveniently Gasil 200 DF from Crosfield Ltd) using 50 to500 μm, preferably 50 to 150 μm sieved fractions.

The flow of the blend for direct compression can be improved byselection of particle size of anhydrous trehalose (AAT or ACT) from the125 to 500 μm, preferably 125 to 250 μm sieved fractions.

In preferred embodiments of the invention an additional excipient may beemployed as a desiccant to enhance the protection for the activeingredients at higher relative humidities. A preferred additionalexcipient is silica gel. A low percentage may be employed, for exampleup to 4%, preferably below 2.5% more preferably 2.4%.

Preferred formulations incorporate one or more disintegrants.Intra-granular or extra-granular disintegrants may be employed. Suitabledisintegrants include starches such as maize starch and rice starch,cross-linked N-vinyl-2-pyrrolidone (CLPVP), sodium starch glycolate,croscarmellose sodium, microcrystalline or microfine cellulose,low-substituted hydroxypropyl cellulose (ie cellulose partiallysubstituted with 2-hydroxypropyl groups, eg less than 25% substituted,preferably 7 to 16% substituted), cross-linked sodium carboxymethylcellulose, swellable ion exchange resins, alginates, formaldehyde-caseinand combinations thereof. A preferred disintegrant is CLPVP for exampleas marketed under the trade names POLYPLASDONE XL and POLYPLASDONEXL-10. A preferred croscarmellose sodium is marketed under the tradename Ac-Di-Sol. A preferred sodium starch glycolate is marketed underthe trade names EXPLOTAB and EXPLOTAB CLV.

The proportion of disintegrant in a tablet may be 0.1% to 30%,preferably 5 to 10%. A mixture of disintegrants may be employed. Anexample of a suitable disintegrant combination is a combination ofmicro-crystalline cellulose with sodium starch glycolate, croscarmellosesodium or CLPVP.

A lubricant may be employed. Any convenient lubricant may be used forexample selected from talc, calcium stearate, stearic acid, hydrogenatedvegetable oil, Lutrol and polyethylene glycol. However use of magnesiumstearate is preferred. Alternatively a water soluble lubricant such assodium stearyl fumarate (eg as sold under the trade name Pruv) may bepreferred. The amount of lubricant may be optional but an amount of 0.1to 2%, preferably 0.5% of magnesium stearate or 0.2% preferably 0.1 to1% or 0.8% sodium stearyl fumarate may be employed.

Any of the commonly used direct compression binders may be employedincluding starch, cellulose derivatives (eg microcrystalline cellulose)dicalcium phosphate, calcium carbonate, magnesium carbonate and sugarssuch as sucrose, glucose, dextrose and lactose. Other suitable binderswhich may be used include Ludipress (a commercial tabletting mixture oflactose and PVP), Kollidon (polyvinyl pyrrolidone (PVP)) andhydroxyethyl starch.

Any suitable filler with a low moisture content may be employed. Use ofa low moisture grade of microcrystalline cellulose, for example as soldunder the trade name Avicel is preferred. This may also serve as awicking agent. The amount of filler may be between broad limits of 10 to90%, more preferably 20 to 50% for example 48%. Additionally andpreferably a diluent such as silicon dioxide may be used. Use of thesilicon dioxide sold under the trade name Gasil is advantageous. Anamount of 2.5 to 30%, preferably 5 to 25% may be used.

The tablet formulations may also include other conventional excipientssuch as flavouring agents, sweeteners, colouring agents, preservativesand suspending aids.

Tablet formulations in accordance with this invention may comply withboth BP and USP specifications and specifically to the BP specificationfor co-amoxiclav regular tablets.

Tablets in accordance with this invention may have a disintegration timeof 60 seconds. Tablet formulations in accordance with this invention maycomprise compacted granulates of a mixture of either active ingredientsor a combination of both active ingredients and an intragranulardisintegrant. The compacted granulates may also include single ormultiple forms of trehalose. In addition the complete formulation may begranulated. The granulates formed in all cases may be subsequentlycompacted together into tablets with an extra-granular disintegrant.Granulates may also be used for tabletting. Preferably the clavulanateand/or amoxycillin is granulated with anhydrous trehalose and silicondioxide. All materials can be dry blended for direct compression.

Tablets in accordance with this invention may contain an effervescentcouple of a conventional type, for example a solid acid and alkalinemetal carbonate or bicarbonate.

Film coated tablets may be provided. Suitable coatings includehydroxypropyl cellulose, acrylate and/or methacrylate copolymers, resinsand the like. Alternatively the coating may be an enteric coating whichis insoluble in acidic gastric juice but soluble in alkaline digestivejuice. Such a coating may enable the antibiotic to pass through thestomach into the duodenum prior to absorption. Suitable enteric coatingsinclude cellulose acetate phthalate.

Double-layered and press-coated tablets may also be provided. In thecase of double-layered tablets the clavulanate and amoxycillin arepreferably in separate layers and the clavulanate layer may contain bothanhydrous trehalose and silicon dioxide. In press-coated tablets thecore may contain the actives, anhydrous trehalose and silicon dioxide,and the coating may contain AT and/or TD.

Granulates of formulations in accordance with this invention may be usedas free flowing granulated formulations provided in sachets or otherpackages. Such granulates may for example be dissolved in water withexcipients, for example sweeteners, thickeners, preservatives andbuffers to form syrup formulations, for example for administration tosmall children. The granulates may also be used in encapsulatedformulations. The capsule may be an entirely conventional capsule,capable of dissolving in the stomach to release its contents, forexample a soft or hard gelatin capsule.

The invention is further described by means of example but not in anylimitative sense.

EXAMPLE 1 Stability of Potassium Clavulanate Blended With DifferentForms of Trehalose

Potassium clavulanate (PC) was blended with either anhydrous amorphoustrehalose or crystalline trehalose dihydrate. The weight ratio oftrehalose to PC was 11.8:1 in both cases. Aliquots of the blendedpowders were stored in vacuum-sealed vials at 40° C. for a maximumperiod of 4 weeks. The results illustrated in FIG. 1 show that there wasno significant loss in PC activity when stored under these conditions inthe presence of different forms of trehalose. Sieved fractions of 50 to500 μm, particularly 100 to 250 μm trehalose powder give advantageousflow and compatibility properties to the tabletting blend.

PC was assayed according to the USP 23 HPLC method:

Column: Hypersil ODS 5μ300×4.6 mm

Detection: 220 nm

Flow Rate: 2 ml min³¹ ¹

Mobile Phase: 50 mm Phosphate Buffer (pH

4.4)/methanol:95/5(v/v)

Injection Volume: 20 μl.

All samples assayed in triplicate.

EXAMPLE 2 Protection of PC From Water Vapour by Amorphous AnhydrcusTrehalose

4 g each of PC and amorphous anhydrous trehalose were weighed out intoopen 60 mm diameter petri dishes. A volume of water (0.4 ml) wasdispensed into a third open petri dish. All 3 petri dishes were placedin a sealed container which was incubated at 25° C. After a period of 24hours all of the water had evaporated within the sealed container.Although the amorphous anhydrous trehalose had significantly increasedin weight by 40% at this time point, there was no increase in weight norany difference in appearance in PC. These results illustrate that theevaporated water molecules were sequestered by the amorphous anhydroustrehalose. This protected the PC from detrimental interactions withwater. ACT was found to take up less water than AAT at lower humidities.Blends of AAT and ACT may be used to optimise these beneficialproperties.

EXAMPLE 3 Disperseble Tablet Formulation

The Following components (except for magnesium stearate) were mixedtogether in a planetary mixer for 10 minutes. The amorphous anhydroustrehalose was passed through a sieve with a nominal aperture size of 500μm prior to addition to the formulation.

% W/W IN WEIGHT PER COMPONENT FORMULATION TABLET (mg) Amoxycillin 3H₂O17.94 287 Potassium clavulanate 9.31 148.9 Microcrystalline cellulose40.25 647.3 (Avicel PH112) Amorphous anhydrous 20.0 320 trehalose Sunettsweetener 1.0 16 (Acesulfame K) Strawberry flavour 1.0 16 Croscarmellosesodium 1.0 16 (Ac-Di-Sol) Sodium starch glycolate 3.0 48 (Explotab CLV)Polyplasdone XL (CLPVP) 5.0 80 Polyvinylpyrollidone 0.8 12.8 (Kollidon30) Magnesium Stearate 0.5 8

The formulation was passed through a sieve with a nominal aperture sizeof 500 μm. Magnesium stearate (after being passed through a sieve with anominal aperture size of 250 μm) was then added and the formulationmixed by tumbling for 5 minutes. Tabletting was performed at ambienttemperature and relative humidity using an F3 Manesty single stagetabletting press with a punch diameter of 20 mm and a compressionsetting of 34.

EXAMPLE 4 Dispersible Tablet Formulation

The following components (except for magnesium stearate) were mixedtogether in a planetary mixer for 10 minutes. The amorphous anhydroustrehalose was passed through a sieve with a nominal aperture rise of 500μm prier to addition to the formulation.

% W/W IN WEIGHT PER COMPONENT FORMULATION TABLET (mg) Amoxycillin 3H₂O22.81 342.11 Potassium clavulanate 10.59 158.82 Silicon dioxide (Aerosil0.03 0.45 200) Microcrystalline cellulose 44.27 664.12 (Avicel PH112)Amorphous anhydrous 10.00 150 trehalose Sunett sweetener 1.0 15(Acesulfame K) Strawberry flavour 1.0 15 Croscarmellose sodium 1.0 15(Ac-Di-Sol) Sodium starch glycolate 3.0 45 (Explotab CLV) PolyplasdoneXL (CLPVP) 5.0 75 Polyvinylpyrollidone 0.8 12 (Kollidon 30) MagnesiumStearate 0.5 7.5

The formulation was passed through a sieve with a nominal aperture sizeof 500 μm. Magnesium stearate (after being passed through a sieve with anominal aperture size of 250 μm) was then added and the formulationmixed by tumbling for 5 minutes. Tabletting was performed at ambienttemperature and relative humidity using an F3 Manesty single stagetable,ting press with a punch diameter of 20 mm and a compressionsetting of 44. The resulting tablets had the following characteristics:

TABLET CHARACTERISTIC VALUE Weight 1.52 g Thickness 5 mm Hardness 8.6 kpDissolution test* passes Disintegration time 1.5 min Content uniformity*passes Dispersion test* passes *Assays performed according to BPspecification for co-amoxiclav regular tablets.

EXAMPLE 5a Dispersible Tablet Formulation

The following components (except for magnesium stearate) were mixedtogether in a planetary mixer for 10 minutes. The amorphous anhydroustrehalose was passed through a sieve with a nominal aperture size of 500μm prior to addition to the formulation.

% W/W IN WEIGHT PER COMPONENT FORMULATION TABLET (mg) Amoxycillin 3H₂O19.87 298.06 Potassium clavulanate 10.59 158.82 Silicon dioxide (Aerosil0.05 0.75 200) Microcrystalline cellulose 47.99 719.87 (Avicel PH112)Amorphous anhydrous 10.00 150 trehalose Sunett sweetener 1.0 15(Acesulfame K) Strawberry flavour 1.0 15 Croscarmellose sodium 1.0 15(Ac-Di-Sol) Sodium starch glycolate 3.0 45 (Explotab CLV) PolyplasdoneXL (CLPVP) 5.0 75 Magnesium Stearate 0.5 7.5

The formulation was passed through a sieve with a nominal aperture sizeof 500 μm. Magnesium stearate (after being passed through a sieve with anominal aperture size of 250 μm) was then added and the formulationmixed by tumbling for 5 minutes. Tabletting was performed a; ambienttemperature and relative humidity using an F3 Manesty single stagetabletting press with a punch diameter of 20 mm and a compressionsettling of 46. The resulting tablets had the following characteristics:

TABLET CHARACTERISTICS VALUE Weight 1.5 g Thickness 5 mm Hardness 11.6kp Dissolution test* passes Disintegration time 1.5 min Contentuniformity* passes Dispersion test* passes *Assays performed accordingto BP specification for co-amoxiclav regular tablets.

EXAMPLE 5b Dispersible Tablet Formulator

The following components selected to give a tablet of 100% were mixedtogether (except for Pruv) in a planetary mixer for 10 minutes. Theamorphous anhydrous trehalose was passed through a sieve with a nominalaperture size of 500 μm prior to addition to the formulation.

COMPONENT % W/W IN FORMULATION Amoxycillin 3H₂O 19.87 Potassiumclavulanate 10.59 Silicon dioxide (Aerosil 0.3 200) Microcrystallinecellulose   27-47.99 (Avicel PH112) Anhydrous trehalose 10-20 Sunettsweetener (Acesulfame 1.0 K) Strawberry flavour 1.0 Croscarmellosesodium (Ac- 5 Di-Sol) Polyplasdone XL (CLPVP) 4 Sodium stearyl fumarate0.5-1   (Pruv) Silicon dioxide diluent  5-30 (Gasil 200 DF)

The formulation was passed through a sieve with a nominal aperture sizeof 50 μm to remove fines. Pruv (after being passed through a sieve witha nominal aperture size of 250 μm) was then added and the formulationmixed by tumbling for 5 minutes. Tabletting was performed at ambienttemperature and relative humidity using an F3 Manesty single stagetabletting press with a punch diameter of 20 mm and a compressionsetting of 46. The resulting tablets showed good dissolution, dispersionand storage stability.

TABLET CHARACTERISTIC VALUE Weight 1.55 g Thickness 5 mm Hardness 8.2 kpDissolution test* passes Disintegration time 1 min Content uniformity*passes Dispersion test* passes *Assays performed according to BPspecification for co-amoxiclav regular tablets.

EXAMPLE 6 Dispersible Tablet Storage Stability

Batches of tablets made in accordance with Example 5 were stored insealed containers, together with commercially available tablets withsimilar levels of actives. Storage was at 40° C. and 75% relativehumidity. After 2 weeks storage, 2 liter stock solutions were preparedusing 10 of each batch of tablets (refer to FIG. 2). It was evident thatthere was marked discolouration in the reference tablet solution whereasthat of the invention tablet remains white. The brown discoloration wasdue to potassium clavulanate inactivation. This indicated that thestability of potassium clavulanate in the invention tablet had beenmarkedly enhanced.

EXAMPLE 7 Dispersable Tablet With Additional Desiccant

Two batchtes with varying amounts of AAT blended with pre-driedexcipients were prepared designated Example 7a and 7b.

One batch included silica gel at 2.4% w/w. This was designated Example7c.

The batches for Examples 7a-c were redried in a Precision Scientificoven at 60° C. for 1 week. Ten tablets of each batch were placed in aminimal head-space glass jar and sealed with Nescoflim prior to testing.Ten tablets were treated identically and placed at 4° C. to act ascontrols. Five tablets were removed from each of the jars and assayed byHPLC for amoxycillin and potassium clavulanate content.

The blend was then tabletted using the Manesty F3 operated manually:

Compression:48.5

fill wt: 1.50-1.51 g

punches 20mm bevel edged

Testing of tablets:

The following specification was applied:

disintegration time: less than one minute.

dispersion test: pass through 710 micron sieve.

hardness: 5-7 kP

residual moisture content (rmc) was determined

The tablets were formulated according to the following method.

A) Pass the 30# AAT and amoxycillin trihydrate through a 30# sieve andmix for 5 mins by hand. Then re-sieve and mix for a further 2 min andset aside.

B) Sieve the Aerosil 200 and potassium clavulanate through a 30# sieveand mix for 5 min. Then re-sieve and mix for a further 5 min.

C) Combine (A) with approximately 75% of the Avicel PH-112 and mix for 5min.

D) Mix in a weigh-boat with a spatula the Sunnett, strawberryhexaflavour, Ac-Di-Sol, Explotab and CL-PVP with the remaining 25% ofthe Avicel.

E) Combine (C) and (D) and mix for 5 min.

F) Combine (E) and (B) and mix for 5 min. Sieve through a 30# sieve andre-mix for a further 5 min.

G) Sieve the magnesium stearate through a 250 micron sieve and mix into(F) with minimal blending for 1 min.

EXAMPLE 7a

Ingredient % w/w mg/tablet weight (g) Amoxycillin. 19.87 298.06 19.873H₂O Potassium Clavulanate 10.59 158.82 10.59 Aerosil 200 0.05 0.75 0.05Avicel-PH112 47.99 719.87 47.99 AAT (30# sieved) 10.00 150 10.00 SunnettAcesulfame K 1.00 15 1.00 Strawberry hexaflavour 1.00 15 1.00 Ac-Di-Sol1.00 15 1.00 Explotab 3.00 45 3.00 CL-PVP 5.00 75 5.00 MagnesiumStearate 0.50 7.5 0.50

EXAMPLE 7b

Ingredient % w/w mg/tablet weight (g) Amoxycillin.3H₂O 19.87 298.06 9.94Potassium Clavulanate 10.59 158.82 5.30 Aerosil 200 0.05 0.75 0.025Avicel-PH112 42.99 322.5 21.50 AAT (30# sieved) 15.00 112.5 7.50 SunnettAcesulfame K 1.00 15 0.50 Strawberry 1.00 15 0.50 Hexaflavour Ac-Di-Sol1.00 15 0.50 Explotab 3.00 45 1.50 CL-PVP 5.00 75 2.5 Magnesium Stearate0.50 7.5 0.25

Example 7b passed all the tests. The rmc was 4.6% w/w.

EXAMPLE 7c

weight Ingredient % w/w mg/tablet (g) Amoxycillin.3H₂O 19.87 298.06 9.94Potassium Clavulanate 10.59 158.82 5.30 Aerosil 200 0.05 0.75 0.025Avicel-PH112 45.59 342 22.80 AAT (30# sieved) 10.00 75 5.00 SyloidAL1-FP 2.40 36 1.20 Sunnett Acesulfame K 1.00 15 0.05 Strawberry 1.00 150.50 hexaflavour Ac-Di-Sol 1.00 15 0.50 Explotab 3.00 45 1.50 CL-PVP5.00 75 2.5 Magnesium Stearate 0.50 7.5 0.25

Example 7c passed the tests. The mean rmc was 5.5% w/w.

HPLC Analysis of Examples 7a-c

The results of HPLC analysis of the drug actives are shown as mean % ofUSP specification for both amoxycillin and potassium clavulanate.

Mean Potassium Clavulanate content 4° C. as % of USP spec 1 month 9M13A98.59 9M16A 97.92 9M18A 100.54 9M19A 98.80 Mean Amoxycillin content as %of USP 4° C. spec 1 month 9M13A 104.07 9M16A 101.53 9M18A 97.47 9M19A95.44

Method of granulate preparation

a) active components were milled and sieved using a 1.0 or 0.7 mmaperture sieve

b) mix for 15 minutes in a blender with the chosen intra-granulardisintegrant (eg CLPVP)

c) the blended mixture was then consolidated using a roller compacter ata controlled pressure (eg 50 KN)

d) the compacted flakes were then granulated in a mill, or granulatedthrough a sieve Fitted with a 1 mm mesh to obtain a suitable sizefraction.

The size of the resultant granulates are preferably in the range 100 μmto 2 mm, suitably around 1 mm+/−0.25 mm. The particle size of theactives in the granulates is preferably in the range 5 μm to 500 μm,especially 5.0 μm to 200 μm.

Suitable disintegrants include those described previously orcombinations thereof. The proportion of intra-granular disintegrant inthe granulate may be 0.1-10 wt % of the granulate, suitably 1.0-9.0 wt%, such as 1.5-4.0 wt %. The proportion of extra-granular disintegrantto total tablet weight may vary between broad limits, for example 0.1-30wt %.

Preferred combinations of components for the tablets of this aspect ofthe invention therefore comprise:

GRANULATE 1 COMPONENT WEIGHT % EXAMPLE Antibiotics 70-99 Amoxycillintrihydrate and/or Potassium clavulanate Disintegrant(s) 0.1-4   CLPVP,microcrystalline cellulose, sodium starch glycolate, croscarmellosesodium Diluent(s)  0-30 trehalose: AT, AAT, TD, ACT or mixtures thereof

TABLET 1 COMPONENT WEIGHT % EXAMPLE Granulate 70+ above Disintegrant(s)0.1-25 CLPVP, microcrystalline cellulose, sodium starch glycolate,croscarmellose sodium Lubricant   0-0.5 Magnesium stearate Excipients to100 acesulfame K, aspartame, flavourings, colour, Silicon dioxide

GRANULATE 2 COMPONENT WEIGHT % EXAMPLE Antibiotics 70-99 Amoxycillintrihydrate and/or Potassium clavulanate Diluent(s) 2.5-30  Silicondioxide, Gasil 200 DF Excipient(s)  0-30 Trehalose: AT, AAT, TD, ACT ormixtures thereof

TABLET 2 COMPONENT WEIGHT % EXAMPLE Granulate 70+ above (1 and/or 2)Disintegrant(s) 0.1-25  CLPVP, microcrystalline cellulose, sodium starchglycolate, croscarmelloe sodium Lubricant 0-1 Sodium stearyl fumaratePruv)

Addditionally, the complete formulation as outlined above, minus thelubricant and extra-granular disintegrant(s) may be compacted.

The compaction of the mixture into granulates may be by conventional drycompaction means, eg pressing, rolling, slugging extrusion etc and asuitable pressure for the compaction process is 20-250 RN eg 30-70 KNpreferably 40-50 KN. It may be necessary to mill and sieve the compactedmixture after compaction in order to achieve a suitable size fraction ofthe granulate as outlined above.

Compression into tablets may be carried out in a conventional manner, egon a conventional tabletting machine.

A specific granulation example is:

GRANULATE COMPONENT WEIGHT % Amoxycillin.3H₂O 19.32 Potassiumclavulanate 10.25 Amorphous anhydrous 10.05 trehalose Microcrystallinecellulose 53.14 (Avicel PH112) Sodium starch glycolate 3.29 (Explotab)Croscarmellose sodium 3.29 (Ac-Di-Sol) Flavouring 0.66

TABLET COMPONENT WEIGHT % Granulate as above 99.48 Magnesium stearate0.52

The components for granulation were blended in a planetary mixer for 10minutes. The Formulation was then compacted by passing it through aKilian eccentric tabletting press fitted with 20 mm diameter punches.The compacted material was subsequently passed through a sieve with anominal mesh size of 1 mm. The resulting material was blended in aplanetary mixer for 5 minutes prior to tabletting. The granulate blendhad the following characteristics:

PHYSICAL CHARACTERISTIC VALUE Bulk volume 2.04 ml/g Bulk density 0.49g/ml Tapped volume 1.52 ml/g Tapped density 0.659 g/ml Flowability 0.989g/s Angle of Repose 41.1 Compressibility 25.53%

Tablets of 20 mm diameter were made using the Kilian eccentrictabletting press. These had the following characteristics:

TABLET CHARACTERISTIC VALUE Weight 1.52 g Thickness 4.55 mm Hardness9.37 kp Disintegration time 1.83 min Dispersion test passes

EXAMPLE 8 Encapsulated Formulation

A granulate or powder blend was prepared using the above methods andmade into a loose compact under gentle pressure. This is subsequentlysealed into gelatin capsules.

EXAMPLE 9 Sachet and Syrup Formulations

A granulate prepared using the above methods was combined withextra-granulate excipients including an extra-granular disintegrant (egCLPVP at 0.1-5% by weight, flavourings (eg lemon, strawberry and/orpeach) at 1.0-15% by weight, sweetener (eg aspartame or acesulfame K) at0.5-2.0% by weight and optionally xanthan gum as a suspending agent at1.0-5.0% by weight.

Additionally, these weights may be made up in a specific volume toproduce a syrup with the required dose levels of antibiotics. To adjustthe syrup to a suitable viscosity and pH, aerosil 200, succinic acidand/or methocel E-15 (dry) may be used.

EXAMPLE 10 Formation of of Bilayered and Press-coated Tablets

Bilayered tablets were made containing the compositions of Examples 3-5,except that magnesium stearate was replaced by sodium stearyl fumarate(Pruv) and 5-20% of the Avicel in these examples was replaced by anequivalent weight of Gasil 200 DF. The two antibiotics were contained inseparate layers in the tablets. The tablets contained the clavulanate,AT (ACT or AAT), disintegrants and Gasil in one layer and theAmoxicillin, flavours, diluents and disintegrants in the other.

Press coated tablets were made according to the procedure of Remington(p1616) containing the compositions as in present Examples 3 to 5,except that magnesium stearate was replaced by Pruv and 5-20% of theAvicel in these examples was replaced by an equivalent weight of Gasil200 DF. The cores of the press-coated tablets contained the antibiotics,flavours, disintegrants, diluent (Gasil 200) and excipients anhydroustrehalose AT (AAT or ACT) whereas the outer layer contained theanhydrous trehalose (AAT or ACT) and optionally favourings.

What is claimed is:
 1. A tablet formulation comprising: a) clavulanic acid or salt thereof; b) amoxycillin; and c) trehalose.
 2. A formulation as claimed in claim 1 wherein the trehalose is anhydrous trehalose.
 3. A formulation as claimed in claim 1 wherein the trehalose is amorphous anhydrous trehalose.
 4. A formulation as claimed in claim 3 wherein the amount of amorphous anhydrous trehalose is 5 to 50%.
 5. A formulation as claimed in claim 4 wherein the amount of amorphous anhydrous trehalose is 7 to 15%.
 6. A formulation as claimed in claim 1, further comprising a desiccant.
 7. A formulation as claimed in claim 6 wherein the desiccant is silica gel.
 8. A formulation as claimed in claim 6 wherein the amount of desiccant is up to 4%.
 9. A formulation as claimed in claim 6 wherein the amount of desiccant is up to 2.5%.
 10. A formulation as claimed in claim 1, further comprising one or more disintegrants selected from the group consisting of starches, cross-linked N-vinyl-2-pyrrollidone, sodium starch glycolate, croscarmellose sodium, microcrystalline or microfine cellulose, low substituted hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose, swellable ion exchange resins, alginates, formaldehyde-casein and mixtures thereof.
 11. A formulation as claimed in claim 10 wherein the proportion of disintegrant in the tablet is 0.1 to 30%.
 12. A formulation as claimed in claim 10 wherein the proportion of disintegrants in a tablet is 5 to 10%.
 13. A formulation as claimed in claim 1, further comprising a lubricant.
 14. A formulation as claimed in claim 13 wherein the lubricant is magnesium stearate in a range from about 0.1% to 2%.
 15. A formulation as claimed in claim 13 wherein the lubricant is water soluble sodium stearyl fumarate.
 16. A formulation as claimed in claim 15 wherein the amount of sodium stearyl fumarate is 0.2%.
 17. A formulation as claimed in claim 1, further comprising silicon dioxide as a diluent.
 18. A formulation as claimed in claim 17 wherein the amount of silicon dioxide is 2.5 to 30%.
 19. A formulation, as claimed in claim 17 wherein the amount of silicon dioxide is 5 to 25%.
 20. A formulation as claimed in claim 1, wherein the ratio of clavulanic acid salt to amoxycillin is equivalent to a ratio of amoxycillin to clavulanic acid of 12:1 to 1:1.
 21. A formulation as claimed in claim 1, wherein the proportion of active ingredients in the tablets is 20 to 90%.
 22. A formulation as claimed in claim 4 wherein the amount of amorphous anhydrous trehalose is about 10%.
 23. A formulation as claimed in claim 10 wherein the proportion of disintegrants in a tablet is about 9%.
 24. A formulation as claimed in claim 15 wherein the amount of sodium stearyl fumarate is 0.1 to 1%.
 25. A formulation as claimed in claim 1, wherein the ratio of clavulanic acid salt to amoxycillin is equivalent to a ratio of amoxycillin to clavulanic acid of about 4:1 to 2:1.
 26. A formulation as claimed in claim 1, wherein the proportion of active ingredients in the tablets is about 30%. 